Bipolar Disorder: Increasing the Effectiveness and Decreasing the Side Effects of Treatment: Page 8 of 11

Divalproex. The study by Bowden and colleagues8 that compared divalproex, lithium, and placebo is the only double-blind, randomized, placebo-controlled trial to analyze the efficacy of divalproex in delaying the onset of a mood episode in bipolar I disorder. Patients who received divalproex had a mean serum level of 84.8 µg/mL by day 30. The minimum and maximum divalproex concentrations over the 52-week maintenance phase were 0.6 and 156 µg/mL, respectively. Study discontinuations were lower in subjects treated with divalproex than in the placebo group, and divalproex was associated with a significantly lower termination rate for recurrent mania or depression.

However, divalproex failed to separate from placebo on the primary end point of time to any mood episode. In addition, there was not a significant difference between divalproex and placebo in the time to a manic episode or time to a depressive episode. The lack of separation for divalproex relative to placebo may have been due to the inclusion of patients with milder forms of bipolar disorder and the low relapse rate of subjects in the placebo group. Furthermore, the study’s strict criteria for mania (MRS score of 16 or higher or need for hospitalization) and depression (antidepressant use or discontinuation from the study because of symptoms) may have reduced the power of the analysis. Divalproex had a significantly greater frequency of tremor and weight gain relative to placebo.

Keck and colleagues51 performed a post hoc analysis of the study by Bowden and colleagues.8 They stratified serum drug concentrations to assess whether any concentration level separated from placebo on primary end points. Patients who received divalproex were stratified into 4 categories (nontherapeutic, low therapeutic, medium therapeutic, and high therapeutic). The divalproex serum ranges used to define these categories were as follows: nontherapeutic, less than 49.9 µg/mL; low therapeutic, 50.0 to 74.9 µg/mL; medium therapeutic, 75.0 to 99.9 µg/mL; and high therapeutic, more than 100.0 µg/mL.

Both the discontinuation rate for mania or depression and the time in maintenance treatment before discontinuation for any reason were superior in the divalproex medium-therapeutic range compared with placebo. The median survival for placebo was 4 months, compared with 8 months for the medium-therapeutic divalproex group. When a similar analysis was performed for lithium, no serum level range differed from placebo. However, this result may have been influenced by insufficient power since the lithium group was half the size of the divalproex group. This study suggests that optimal effectiveness in preventing relapses and achieving acceptable tolerability occurs in the medium therapeutic range of 75 to 99.9 µg/mL.